The Foxo family of transcription factors plays a pivotal role in longevity in invertebrates and is critical for cellular responses to oxidative stress in mammalian cells. The overall goal of this proposal is to understand the molecular mechanisms by which mammalian Foxo factors control the balance between neuronal death and survival in response to oxidative stress stimuli. FoxoS is the Foxo isoform that is the most highly expressed in the nervous system in mammals. In response to oxidative stress stimuli, FoxoS interacts with Sirtl, a member of the Sir2 family of deacetylases that extend longevity in invertebrates. We have also shown that FoxoS is part of high molecular weight complexes, suggesting that other proteins may also regulate FoxoS functions. However, the molecular mechanisms that allow Sirtl and FoxoS to interact and to control cellular functions in response to oxidative stress are not well characterized. To gain insight into how the Foxo3-Sirt1 protein complexes regulate the responses to oxidative stress in neurons, we propose the following specific aims: 1. To determine the mechanisms of interaction between FoxoS and Sirtl in neurons 2. To examine the importance of the Foxo3-Sirt1 complex in preventing neuronal death We will use a combination of biochemical, molecular, and cellular approaches to develop these aims. These experiments will provide critical insight into the mechanisms by which FoxoS translates information about oxidative stress into cellular responses in neurons. Uncovering the mechanisms underlying the interaction between FoxoS and Sirtl should provide insights into the factors that control longevity and regeneration in the normal aging nervous system as well as in age-related neurodegenerative diseases.